Restrictive cardiomyopathy (RC) is characterized by decreased compliance of myocardium and impaired diastolic filling of the ventricle with intact systolic function. Symptoms include exercise intolerance, anasarca and chronic atrial fibrillation. RC is usually sporadic, although it can occur in familial form secondary to amyloidosis or hemochromatosis in an autosomal dominant fashion. Abnormal accumulation of desmin, an intermediate filament protein that is a major component of the cytoskeleton in myocytes, is frequently found in RC. We have a large 4-generation family in which RC segregates as an autosomal dominant trait. Of the 34 family members, 19 were diagnosed as having RC, and we have collected DNA from 24. Age of onset ranges from 3 to 50 years. Amyloidosis and hemochromatosis were excluded and thus the molecular basis of RC in this family is still unknown. Immunohistochemical and electron microscopic studies in one patient's heart tissue showed abnormal granular deposits of desmin throughout the cytoplasm, rather than the normal pattern of 10 nm intermediate filaments located at the level of the Z bands. To test the hypothesis that the desmin gene causes RC, Northern blot analysis of the patient in heart tissue was performed, which demonstrated that desmin gene expression is normal in affected heart. This suggests that the accumulation of desmin is due to post-translational effects. In addition, genetic linkage analysis was performed, which showed that RC in this family is not caused by a structural abnormality in the desmin gene. A set of cytoskeleton and extracellular matrix genes was also tested for linkage and found negative. We are pursuing biochemical characterization of this family, as well as linkage analysis to other possible candidate genes and via a genome-wide linkage study. The identification of the RC gene will add to our knowledge about development and long-term function of the heart.